Understanding the Mechanism of Mucosal Immunotherapy

描述(申请人提供)：食物过敏，一种口服耐受性的异常，在美国发生在6%的儿童和3.5%的成年人中。花生过敏是最常见的食物过敏之一；大多数儿童在生命早期就会患上这种过敏，不会长大就戒掉，并面临严重的、致命的过敏反应的风险。目前还没有针对花生过敏的积极治疗方法，但我们正在与其他人一起开发特定类型的免疫疗法，使这些患者不再对花生过敏。这一建议的意义是基于我们的里程碑式研究，这些研究检查了花生口服免疫疗法(OIT)的效果，这些研究表明，花生过敏患者在治疗(脱敏)过程中可以摄入的花生数量大幅增加，在某些情况下，当停止治疗时，还会导致长期的临床耐受。我们已经确定了这些受试者中嗜碱粒细胞/肥大细胞反应性、抗原特异性T细胞反应和系统体液免疫反应的初步变化。我们的假设是，花生OIT会改变嗜碱性粒细胞/肥大细胞的早期信号通路，导致临床脱敏，然后由于过敏原特异性T细胞和B细胞的相互关联的变化而形成临床耐受。这项建议的长期目标是更好地了解接受过敏原免疫治疗的幼儿对食物的口腔耐受性发展的机制。为了实现这一目标，我们的具体目标如下：目的1：确定OIT导致花生过敏受试者嗜碱/肥大细胞对花生OIT的低反应性的机制(S)；目的2：确定花生变应原特异性T细胞的频率和表型以及Treg细胞的抑制功能，这与临床对花生的耐受性有关；目的3：确定OIT中花生特异性粘膜和全身体液免疫反应对临床耐受性的影响。这些研究将有助于我们确定脱敏状态的机制和持久性，从而有助于OIT后对食物的耐受性的发展。花生过敏的治疗是迫切需要的，这些研究的完成将为OIT和其他类型的治疗方法的开发提供强有力的科学基础，希望产生对花生和其他食物的长期临床耐受性。

DESCRIPTION (provided by applicant): Food allergy, an aberration of oral tolerance, occurs in 6% of children and 3.5% of adults in the United States. Peanut allergy is one of the most common food allergies; most children develop this allergy early in life, do not outgrow it and are at risk for severe and life-ending anaphylactic reactions. Currently there is not a proactive treatment for peanut allergy but we along with others are developing specific types of immunotherapy that will cause these patients to be no longer allergic to peanuts. The significance of this proposal is based on our landmark studies that have examined the effects of peanut oral immunotherapy (OIT) showing a substantial increase in the amount of peanut that a peanut allergic patient can ingest while on therapy (desensitization) and in some cases causing long-term clinical tolerance when the therapy is discontinued. We have identified initial changes in basophil/mast cell reactivity, antigen-specific T cell responses and systemic humoral immune responses in these subjects. Our hypothesis is that peanut OIT will alter the early signaling pathways of basophils/mast cells causing clinical desensitization and then clinical tolerance will develop because of the interrelated changes in allergen-specific T- and B-cells. The long-term goal of this proposal is to better understand the mechanism of the development of oral tolerance to foods in young children treated with allergen immunotherapy. To accomplish this goal our specific aims are the following: Aim 1: Determine the mechanism(s) by which OIT induces hyporesponsiveness in basophils/mast cells in peanut allergic subjects on peanut OIT, Aim 2: Determine the peanut allergen-specific CD4+ T cell frequencies and phenotypes, as well as the suppressive function of Treg cells, that are associated with the development of clinical tolerance to peanuts, Aim 3: Determine the effect of peanut-specific mucosal and systemic humoral immune responses in OIT on clinical tolerance. The studies will help us identify the mechanism and durability of the desensitized state and then the development of tolerance to foods after OIT. A treatment for peanut allergy is critically needed, the completion of these studies will provide a strong scientific basis for the development of OIT and other types of therapy that hope to produce long-term clinical tolerance to peanuts and other foods.